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Epithelial oestrogen receptor ? is dispensable for the development of oestrogen-induced cervical neoplastic diseases.

ABSTRACT: Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa) development. Oestradiol (E2 ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin (K14) promoter. E2 mainly functions through oestrogen receptor ? (ER?). However, the role of ER? in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ER?-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not in the stroma. We found that E2 induced cervical epithelial cell proliferation in epithelial ER?-deficient mice. We also found that E2 promoted the development of CIN and CxCa in epithelial ER?-deficient K14E7 mice and that all neoplastic epithelial cells were negative for ER?. In addition, proliferation indices were similar between ER?- and ER?+ CxCa. These results indicate that epithelial ER? is not necessary for E2 -induced CIN and CxCa. Taking these findings together, we conclude that stromal ER? rather than epithelial ER? mediates oncogenic E2 signalling in CxCa. Our results support stromal ER? signalling as a therapeutic target for the disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

SUBMITTER: Son J

PROVIDER: S-EPMC5959269 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Epithelial oestrogen receptor α is dispensable for the development of oestrogen-induced cervical neoplastic diseases.

Son Jieun J Park Yuri Y Chung Sang-Hyuk SH

The Journal of pathology 20180403 2

Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa) development. Oestradiol (E<sub>2</sub> ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin (K14) promoter. E<sub>2</sub> mainly functions through oestrogen receptor α (ERα). However, the role of ERα in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERα-co ...[more]

PMID: 29532467

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Project description:BackgroundCervical carcinomas are second most frequent type of women cancer. Success in diagnostics of this disease is due to the use of Pap-test (cytological smear analysis). However Pap-test gives significant portion of both false-positive and false-negative conclusions. Amendments of the diagnostic procedure are desirable. Aetiological role of papillomaviruses in cervical cancer is established while the role of cellular gene alterations in the course of tumor progression is less clear. Several research groups including us have recently named the protein p16INK4a as a possible diagnostic marker of cervical cancer. To evaluate whether the specificity of p16INK4a expression in dysplastic and neoplastic cervical epithelium is sufficient for such application we undertook a broader immunochistochemical registration of this protein with a highly p16INK4a-specific monoclonal antibody.MethodsParaffin-embedded samples of diagnostic biopsies and surgical materials were used. Control group included vaginal smears of healthy women and biopsy samples from patients with cervical ectopia. We examined 197 samples in total. Monoclonal antibody E6H4 (MTM Laboratories, Germany) was used.ResultsIn control samples we did not find any p16INK4a-positive cells. Overexpression of p16INK4a was detected in samples of cervical dysplasia (CINs) and carcinomas. The portion of p16INK4a-positive samples increased in the row: CIN I - CIN II - CIN III - invasive carcinoma. For all stages the samples were found to be heterogeneous with respect to p16INK4a-expression. Every third of CINs III and one invasive squamous cell carcinoma (out of 21 analyzed) were negative.ConclusionsOverexpression of the protein p16INK4a is typical for dysplastic and neoplastic epithelium of cervix uteri. However p16INK4a-negative CINs and carcinomas do exist. All stages of CINs and carcinomas analyzed are heterogeneous with respect to p16INK4a expression. So p16INK4a-negativity is not a sufficient reason to exclude a patient from the high risk group. As far as normal cervical epithelium is p16INK4a-negative and the ratio p16INK4a-positive/ p16INK4a-negative samples increases at the advanced stages application of immunohisto-/cytochemical test for p16INK4a may be regarded as a supplementary test for early diagnostics of cervical cancer.

Project description:Estrogen is a risk factor for breast cancer, yet its mechanism in the initiation of this disease is not clear. Here we use a model of estrogen-mediated malignant transformation of MCF-10F cells to identify the temporal acquisition of changes in genome structure and gene expression that correspond to the progressive transformed phenotype culminating in tumorigenesis. Genomic DNA and total RNA were isolated from MCF10F, trMCF (MCF10F transformed by 70 nM 17-beta estradiol), bsMCF (trMCF selected by Boyden chamber, tumorigenic), bcMCF(clones of bsMCF), and caMCF (cells from tumors of bsMCF grown in SCID mice). The Affymetrix 100k SNP and HG-U133_Plus_2 chips were used for genotyping and gene expression analyses. Changes in chromosomal copy number and loss of heterozygosity were progressive. Gross changes were rarely observed in the trMCF10F cells; the earliest was a gain in chromosome 1p, 1p36.12-1p36.21. In the bsMCF and their sub-clones bcMCF, additional gains were seen in chromosomes 1p, 1p36.12-1pter, 5q, 5q21.1-5q35.3, and 13q, 13q21.32-13q34; losses were detected in chromosomes 4 and 8p, 8p11.1-8p23.1. In the caMCF, additional losses were seen in chromosomes 3p, 3p12.1-3p14.1, 9p, 9p22.1-9p24.3, and 18q, 18q11.2-18q23. Using microarray analysis we were able, in some cases, to narrow the regions of interest and their associated candidate cancer genes. The observation of progressive genomic changes, along with the tumor phenotype of a poorly differentiated adenocarcinoma, indicate an underlying mechanism common to breast cancer development in humans, and adds to the evidence indicating that estrogens are mutagenic and contribute early to the process of breast cancer. Experiment Overall Design: Human MCF-10F cells were transformed by 70nM 17-beta-estradiol. The transformed cells were selected by Boyden chamber. The selected cells were injected into SCID mice and also cloned and expanded. The thus grown tumors were harvested for cell culture. Genomic DNA and total RNA were isolated from cell lines in each step for 100K SNP and gene expression microarray assay.

Project description:IntroductionOestrogens can mediate some of their cell survival properties through a nongenomic mechanism that involves the mitogen-activated protein kinase (MAPK) pathway. The mechanism of this rapid signalling and its dependence on a membrane bound oestrogen receptor (ER), however, remains controversial. The role of G-protein-coupled receptor and epidermal growth factor (EGF) receptor in an ER-independent signalling pathway modulated by oestrogen was investigated.MethodsER-positive and ER-negative breast cancer cell lines (MCF-7 and SKBR3) and primary breast cancer cell cultures were used in this study. Cell proliferation was assessed using standard MTT assays. Protein and cAMP levels were detected by Western blotting and ELISA, respectively. Antigen localization was performed by immunocytochemistry, immunohistochemistry and immunofluorescence. Protein knockdown was achieved using small interfering RNA technologies.ResultsEGF and oestrogen, alone and in combination, induced cell proliferation and phosphorylation of MAPK proteins Raf and ERK (extracellular signal regulated kinase)1/2 in both ER-negative SKBR3 and ER-positive MCF-7 human breast cancer cell lines. Increased Raf phosphorylation was also observed in primary human breast cultures derived from ER-positive and ER-negative breast tumours. Oestrogen induced an increase in intracellular cAMP in ER-negative SKBR3 human breast cancer cells. Oestrogen-mediated cell growth and phosphorylation of MAPK was modified by the EGF receptor antagonist AG1478, the G-protein antagonist pertussis toxin, and the angiotensin II receptor antagonist saralasin. Knockdown of angiotensin II type 1 receptor (AT1) protein expression with small interfering RNA attenuated oestrogen-induced Raf phosphorylation in ER-negative cells. AT1 receptor was found to be expressed in the cell membrane of breast tumour epithelial cells.ConclusionThese findings provide evidence that, in breast cancer cells, oestrogen can signal through AT1 to activate early cell survival mechanisms in an ER-independent manner.

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Epithelial oestrogen receptor ? is dispensable for the development of oestrogen-induced cervical neoplastic diseases.

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Epithelial oestrogen receptor α is dispensable for the development of oestrogen-induced cervical neoplastic diseases.

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